Loss of direct adrenergic innervation after peripheral nerve injury causes lymph node expansion through IFN-γ

Peripheral nerve injury can cause debilitating disease and immune cell–mediated destruction of the affected nerve. While the focus has been on the nerve-regenerative response, the effect of loss of innervation on lymph node function is unclear. Here, we show that the popliteal lymph node (popLN) receives direct neural input from the sciatic nerve and that sciatic denervation causes lymph node expansion. Loss of sympathetic, adrenergic tone induces the expression of IFN-γ in LN CD8 T cells, which is responsible for LN expansion. Surgery-induced IFN-γ expression and expansion can be rescued by β2 adrenergic receptor agonists but not sensory nerve agonists. These data demonstrate the mechanisms governing the pro-inflammatory effect of loss of direct adrenergic input on lymph node function.

Brain injury instructs bone marrow cellular lineage destination to reduce neuroinflammation

Acute brain injury mobilizes circulating leukocytes to transmigrate into the perivascular space and brain parenchyma. This process amplifies neural injury. Bone marrow hematopoiesis replenishes the exhausted peripheral leukocyte pools. However, it is not known whether brain injury influences the development of bone marrow lineages and how altered hematopoietic cell lineages affect neurological outcome. Here, we showed that bone marrow hematopoietic stem cells (HSCs) can be swiftly skewed toward the myeloid lineage in patients with intracerebral hemorrhage (ICH) and experimental ICH models. Lineage tracing revealed a predominantly augmented hematopoiesis of Ly6Clow monocytes infiltrating the ICH brain, where they generated alternatively activated macrophages and suppressed neuroinflammation and brain injury. The ICH brain uses β3-adrenergic innervation that involves cell division cycle 42 to promote bone marrow hematopoiesis of Ly6Clow monocytes, which could be further potentiated by the U.S. Food and Drug Administration–approved β3-adrenergic agonist mirabegron. Our results suggest that brain injury modulates HSC lineage development to curb distal brain inflammation, implicating the bone marrow as a unique niche for self-protective neuroimmune interaction that might be exploited to obtain therapeutic effects.

Association of tyrosine hydroxylase expression in brain and tumor with increased tumor growth in sympathectomized mice

Objective Lymphocytes express tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine, norepinephrine and epinephrine. This suggests a broader role for cathecholamines in lymphocyte function, as well as the potential secretion of catecholamines by tumors of lymphoid origin. Our aim was to evaluate the expression of Th by murine lymphoma cells in an in vivo mouse model. For this, L5178Y-R lymphoma cells were implanted in nerve-intact and sympathectomized male BALB/c mice. Relative Th gene expression in tumor and brain was determined by quantitative PCR. Body composition, tumor volume, and plasma TH1/TH2/TH17 cytokines were also evaluated as markers of tumor-host condition and anti-tumor immune response in absence of adrenergic innervation. Results We found a significant (p = 0.045) 3.3-fold decrease of Th gene expression in tumor and a non-significant (p = 0.60) 6.9-fold increase in brain after sympathectomy. Sympathectomized mice also showed a significant increase in tumor mass at days 18 (p = 0.032) and 28 (p = 0.022) and increased interscapular fat (p = 0.04). TH1/TH2 and TH17 cytokines levels in plasma from sympathectomized tumor-bearing mice were not different from control mice. Conclusion The L5178Y-R lymphoma does not express Th during in vivo progression.

Choroidal vascularization and adrenergic innervation qualitative findings obtained with induced fluorescence preparations and optical coherence tomography angiography: possible correlations and perspectives

Background Recent advances in optical coherence tomography (OCT) technology allow a more accurate choroidal visualization. The aim of this study is to provide histochemical analysis with induced fluorescence images of the choroidal stromal, vascular and nerve network, highlighting possible correspondences with OCT and OCT angiography (OCT-A) analysis. Methods The material examined with a histochemical process of induced fluorescence through condensation of biologically active monoamines with glyoxylic acid was obtained from 6 eyes enucleated for malignant melanoma and ciliary body neoplasia. The resulting images have been qualitatively compared with OCT and OCT-A choroidal images obtained from 10 volunteers, in order to identify possible relationships. Choriocapillary segmentation was performed automatically through the embedded analysis software, while segmentation of Sattler’s and Haller’s layers was performed through a manual method. Results Histochemical analysis provided accurate visualization of choroidal adrenergic innervation across all layers and its relationships with blood vessels and melanocytes. The above structures were not visualized at OCT and OCT-A which provided good visualization of blood vessels in Sattler’s and Haller’s layers as well-delimited hyporeflective areas. Decorrelation signal was not detected in OCT-A analysis due to low blood flow velocity in external choroidal layers. Conclusions The choroid is an extremely dynamic structure which deserves to be analyzed in vivo since it is involved in the pathogenesis of several ocular conditions. Direct evaluation of the activity of choroidal nerves and melanocytes is still not possible with OCT and OCT-A, even if they are capable of providing a satisfactory representation of choroidal vascularization.